Substituted dioxocyclohexyl-p-toluenesulfonamides



United States Patent Int. Cl. C07c 143/78 US. Cl. 260-556 3 ClaimsABSTRACT OF THE DISCLOSURE p-Toluenesulfonamides of the formula whereinR and R are each independently selected from the group consisting ofhydrogen or lower alkyl. These compounds are intermediates forpreparation of anthelmintic4-(1,2,3,4,5,6,7,8-octahydro-1,8-dioxo-9-acridanyl)-benzenesulfonamides.

RELATED APPLICATIONS This application is a division of application Ser.No. 751,337, filed Aug. 9, 1968, now Pat. No. 3,454,577, which in turnis a division of application Ser. No. 507,053, filed Nov. 9, 1965, nowPat. No. 3,414,587.

DETAILED DESCRIPTION This application relates to the condensation ofp-sulfamoylbenzaldehyde with 1,3-cyclohexanedione or with 5,5-di-loweralkyl-substituted-l,3-cyclohexanedione. More particularly, the processof this invention can be traced with respect to the following schematicdiagram.

In Formula VI below the symbol R represents lower alkyl or phenyl; R andR are each independently selected Patented Oct. 27, 1970 "Ice SOzNHr (H)CHO (I) IT! SOzNHz SOzNHz O O O i O u n u 5 11 R1 R1 R1 R =0 0.. R2 R2R2 0 R2 (III) (IV) 1 a l S|O2NH2 ?O2NHCOR O O O p O [I I ll CH OH R, N\RR 112 X B2 from the group consisting of hydrogen and lower alkyl; andX is oxygen or Like symbols in Formulas II through V have like meanings.'Ihe condensation products represented by Formulas IV and V and theacylated derivatives thereof represented by Formula VI have not beenpreviously disclosed in the art. The intermediates of Formula III arealso novel compounds and thus constitute a part of this invention.

As illustrated by the schematic diagram above, condensation ofp-sulfamoylbenzaldehyde with a 1,3-cycl0- hexanedione of Formula IIgives directly the novel Xanthenylbenzenesulfonamide of Formula IV.5,5-di-1ower alkyl-1,3-cyclohexanediones suitable for use as startingmaterials are for example, the 5,5-dimethyl-, 5,5-diethyl-,S-methyl-S-ethyl-derivatives and the like. The condensation reaction issuitably carried out at a slightly elevated temperature, i.e., at atemperature between about room temperature and about 100 C. Thecondensation can be conveniently effected in the presence of glacialacetic acid or in any inert solvent, suitably in an aqueous solvent. Theamounts of reactants employed are not critical, though to assure optimumyields, it is preferred to utilize at least 2 moles of thecyclohexanedione per mole of sulfamoylbenzaldehyde.

The acridanyl benzenesulfonamides of Formula V are prepared from thecorresponding compounds of Formulas III or IV by treatment with ammonia.The treatment with ammonia is suitably effected at an elevatedtemperature, i.e., a temperature between about room temperature andabout 100 or higher and at an elevated pressure. Suitably the reactionis carried out in a pressure vessel, i.e., an autoclave.

As illustrated by the schematic diagram above, the compounds of FormulasIV and V are also accessible by an alternative route via the novelintermediates of Formula III. When the condensation reaction is carriedout under mild conditions, e.g., room temperature in aqueous alkanol,e.g., ethanol, etc., the intermediates of Formula III can be isolatedfrom the reaction product. Compounds of Formula III are readilyconverted to compounds of Formula IV by dehydration, for example, byheating with or without a dehydrating agent such as sulfuric acid,polyphosphoric acid, acetic anhydride and the like. Compounds of FormulaV can be obtained directly by treatment of the corresponding Formula IIIintermediates with ammonia at elevated temperature and pressures. Theconversion of intermediates of Formula III to the correspondingxanthenyl derivatives of Formula IV can be accomplished either bytreating the intermediate formed in situ or by isolating theintermediate and subsequently converting it to the novel end products.The acylated derivatives of Formula VI are prepared by treating thecorresponding Formula IV or Formula V compound with any of the ordinaryacylating agents such as, for example, alkanoic anhydrides, e.g., aceticanhydride, etc.; acyl halides, such as alkanoyl halides, e.g., acetylchloride, propionyl chloride, etc., aryl halides, e.g., benzoylchloride, etc.

The novel compounds of Formula VI are useful in combating helminticpathogens such as A. Galli, H. Gallinae, etc. More particularly, thecompounds have been found to possess larvicidal and larvistatic activityagainst A. Galli and therefore are especially useful in the prophylactictreatment of helminthiasis. The compounds of the present invention areeffective when administered via poultry feed at levels from about 0.0025percent to about 0.1 percent by weight of feed stock. Higher levels canof course be employed. The novel compounds of this invention can beadministered to poultry orally as a component to the feed or thedrinking water. This can be accomplished by dispensing the compound ineither a liquid or solid injestible. Conveniently, the drug can beadministered by incorporating into feed rations such amounts as willprovide a daily minimum intake sufiicient to provide helminticprophylaxis. These compounds can be, for example, combined with suchfeed elements as corn meal, ordinary grain, mash, scratch and othernormal or commercial feed rations which may also contain additionalsubstances such as chemotherapeutic and antibiotic agents compatiblewith the anthelmintic compounds of this invention, for example, theanthelmintics of the invention could be combined with compatiblecoccidiostats for combined anthelmintic anti-coccidiosis treatment.

The compounds of this invention can be converted to their base salts andsuch salts with pharmaceutically acceptable bases are also included inthis invention. Suitable bases are, for example, alkaline metalhydroxides, e.g., sodium hydroxide, etc.

The following examples are illustrative of the invention. Alltemperatures are in degrees centigrade.

4 EXAMPLE 1 Preparation of4-(l,2,3,4,5,6,7,8-octahydro-3,3,6,6-tetramethyl-1,8-dioXo-9-xanthenyl)benzenesulfonamide Twenty-eight grams of p-sulfamoylbenzadehyde and 45g. of 5,5 dimethyl 1,3-cyclohexanedione were suspended in 180 ml. ofglacial acetic acid and the mixture was heated on the steambath for 18hours. During the heating, a clear solution was obtained, followed byslow deposition of crystals. After cooling, the crystals were collectedby filtration, washed with water, and air-dried. After recrystallizationfrom ethanol-water, the product melted at 289-290 (dec.).

By an alternate method, a solution of 3.7 g. of psulfamolbenzaldehyde in50 ml. of hot water was added to a solution of 6 g. of5,5-dimethyl-1,3-cyclohexanedione in ml. of hot water. White solidsprecipitated immediately. The suspension was refluxed with stirring for3 hours, and the product collected by filtration. Afterrecrystallization from ethanol-water, the crystals melted at 288-290(dec.).

6,6 tetramethyl-1,8-dioxo-9-xanthenyl)benzenesulfonamide Fifty-sevengrams of 4-(1,2,3,4,5,6,7,8-octahydro-3,3, 6,6-tetramethyl-1,8 dioxo9-xanthenyl)benzenesulfonamide was suspended in 570 ml. of aceticanhydride and the mixture refluxed for 5 hours. After about 2 hours, aclear solution was obtained. The cooled solution was added slowly to 3liters of ice-water, and the slurry stirred for about 2-3 hours. Thesolids were collected by filtration, washed with water, and air-dried.The N-acetyl-4-(l,2,3,4,5,6,7,8-octahydro-3,3,6,6 tetramethyl 1,8 dioxo9 xanthenyl)benzensulfonamide thus obtained was recrystallized bydissolving it in one liter of hot ethanol, treating the solution withactivated charcoal, and adding 2 liters of water to the filtrate. Thewhite crystalline product melted at 189- 191.

EXAMPLE 3 of 4 (1,2,3,4,5,6,7,8-octahydro 1,8-dioxo-9- Twelve grams of1,3-cyclohexanedione and 9.2 g. of p-sulfamoylbenzaldehyde weredissolved in 65 ml. of glacial acetic acid and the solution heated onthe steambath for 18 hours. After cooling, the precipitated crystalswere collected by filtration, washed with water, and airdried. Afterrecrystallization from dimethylformamidewater, the product melted at304-306 (dec.).

By an alternate method, 4.8 g. of 1,3-cyclohexanedione was added to asolution of 3.7 g. of p-sulfamoylbenzaldehyde in 55 ml. of hot water.After a few minutes solids precipitated, and the suspension was refluxedfor 3 hours. The product was collected by filtration and recrystallizedfrom dimethylformamide-water. M.P. 305306 (dec.).

EXAMPLE 4 Preparation of a x-bis(4,4-dimethyl-2,6-dioxocyclohexyl)-p-toluenesulfonamide To a solution of 11.2 g. of5,5-dimethyl-l,3-cyclohexanedione in a mixture of 600 ml. of water andml. of ethanol was added a solution of p-sulfamoylbenzaldehyde in 100ml. of ethanol. An additional 100 ml. of ethanol was added to achievecomplete homogenization and the solution was allowed to stand at roomtemperature for 3 days. The crystals were collected by filtration,washed with water and dried under reduced pressure at 50". Afterrecrystallization from acetone-petroleum ether, cant-bis (4,4 dimethyl2,6 dioxocyclohexyl)-p-toluenesulfonamide melted at 196-l97 (dec.).

EXAMPLE Preparation of4-(1,2,3,4,5,6,7,8-octahydro-3,3,6,6-tetramethyl-1,8-dioxo-9-acridanyl)benzenesulfonamideTen grams of (1,0; bis(4,4dimethyl-2,6-dioxocyclohexyl)-p-toluenesulfonamide was suspended in 150ml. of methanol, the mixture was cooled to 20 and saturated withammonia. The clear solution thus obtained was heated in an autoclave forhours at 100. On cooling, 5 g. of crystals were obtained and collectedby filtration. Concentration of the mother liquors yielded additionalcrystals. After recrystallization from ethanol-water, 4-(1,2,3,4,5,6,7,8 octahydro-3,3,6,6-tetramethyl-1,8-dioxo-9-acridanyl)benzenesulfonamide was obtained as yellow crystals melting at305-308 (dec.).

EXAMPLE 6 Preparation of (1,04bis(2,6-dioxocyclohexyl)-p-toluenesulfonamide To a solution of 10.4 g.of 1,3-cyclohexanedione in 200 ml. of water was added a solution of 8 g.of p-sulfamoylbenzaldehyde in 100 ml. of ethanol, and the mixture wasallowed to stand at room temperature for 3 days. The crystals werecollected by filtration, washed with water and dried under reducedpressure at 50. After recrystallization from dimethylformamide-water,oz,ubiS(2,6-dioxocyclohexyl)-ptoluenesulfonamide sintered at about 240and melted at 303304.

EXAMPLE 7 Preparation of 4 (1,2,3,4,5,6,7,8-octahydro-1,8-dioxo-9-acridanyl)benzenesulfonamide Ten grams ofa,abis(2,6-dioxocyclohexyl)-p-toluenesulfonamide was suspended in 150ml. of ethanol and the mixture was saturated with ammonia at 20. Theclear solution thus obtained was kept in an autoclave at roomtemperature for 60 hours. After removal of the solvent under reducedpressure, the residue was dissolved in a minimum of ethanol and filteredfrom some insolubles. To the clear filtrate was added water untilturbidity and the solution was allowed to stand at room temperature for24 hours. The crystals were collected by filtration, washed and driedunder reduced pressure. From the mother liquors an additional amount ofcrystals was obtained. After recrystallization fromdimethylformamide-water, the yellow crystals melted at 308-310 (dec.).

EXAMPLE 8 Preparation of N -acetyl-4-(1,2,3,4,5,6,7,8-octahydro-3,3,

6,6 tetramethyl-1,8-dioxo-9-acridanyl)benzenesulfonamide Three grams of4 (1,2,3,4,5,6,7,8-octahydro-3,3,6,6- tetramethyl 1,8dioxo-9-acridanyl)benzenesulfonamide was suspended in 40 ml. of aceticanhydride and the mixture was refluxed for 18 hrs. After cooling, thecrystals were collected by filtration, washed and air-dried. Afterrecrystallization from ethanol-water, the yellow crystalline productmelted at 281-283 (dec.).

EXAMPLE 9 Preparation of N-acetyl-4-(1,2,3,4,5,6,7,8-octahydro-1,8-

dioxo-9-xanthenyl)benzenesulfonamide Seventeen grams of4-(1,2,3,4,5,6,7,8-octahydro-1,S-dioxo-9-xanthenyl)benzenesulfonamidewas suspended in 170 ml. of acetic anhydride and the mixture wasrefluxed with stirring for 6 hours. After cooling, the crystals werecollected by filtration and air-dried. After recrystallization fromethanol-water, the white crystalline product melted at 274-275 (dec.).

EXAMPLE 10 Preparation of N-propionyl-4-(1,2,3,4,5,6,7,8-octahydro-3,3,6,6 tetramethyl 1,8-di0xo-9-xanthenyl)benzenesulfonamide Fifteengrams of 4 (1,2,3,4,5,6,7,8-octahydro-3,3,6,6-

tetramethyl 1,8-dioxo-9-xanthenyl)benzenesulfonamide was suspended inml. of propionic anhydride and the mixture was heated at 150 for 6hours. After cooling, the clear solution was added to 2 liters of waterand the slurry stirred at room temperature for 8 hours. The solidproduct was collected by filtration, washed with water and airdried.After recrystallization from aqueous ethanol, the product melted at233-234".

EXAMPLE 11 Preparation of N-butyryl 4 (1,2,3,4,5,6,7,8-octahydro-3,3,6,6 tetramethyl 1,8-dioxo-9-xanthenyl)benzenesulfonamide Fifteengrams of 4 (1,2,3,4,5,6,7,8-octahydro-3,3,6,6- tetramethyl1,8-dioxo-9-xanthenyl)benezenesulfonamide was suspended in 100 ml. ofbutyric anhydride and the mixture was heated at 150 for 6 hours. Aftercooling, the clear solution was added to 3 liters of water containing200 ml. of 40 percent sodium hydroxide. The mixture was stirred at roomtemperature for 3 hours and acidified with cone. hydrochloric acid to pH6. The precipitated amorphous solid was collected by filtration, washedwith water and redissolved in 3 liters of water containing 100 ml. of 40percent sodium hydroxide. After acidifications with cone. hydrochloricacid to pH 3, the precipitated solids were collected by filtration,washed with water and dried under reduced pressure at 50.Recrystallization from benzene yielded white rosettes melting at 163165and containing 1 mole of benzene.

Recrystallization of this compound from ethyl acetatepetroleum etheryielded N-butyryl 4 (1,2,3,4,5,6,7,8- octahydro 3,3,6,6tetramethyl-1,8-dioxo-9-xanthenyl) benzenesulfonamide free of solvent,M.P. 203-205".

EXAMPLE 12 Preparation of N-benzoyl-4-(l,2,3,4,5,6,7,8-octahydro-3,3,6,6 tetramethyl 1,8-dioxo-9-xanthenyl)benzenesulfonamide Thefollowing premix formulation incorporating N-acetyl-4-(1,2,3,4,5,6,7,8-octahydro-3,3,6,6 tetramethyl-1,8-dioxo-9-xanthenyl)benzenesulfonamide is illustrative of anthelminticformulations containing the novel compounds of this invention.

20 Percent premix for animal use Grams/kiloN-acetyl-4-(1,2,3,4,5,6,7,8-octahydro-3,3,6,6-

tetramethyl-1,8 -dioxo-9-xanthenyl) benzenesulfonamide Corn germ meal831 Drew Oil 1400 44 Total weight 1000 Procedure (1) The corn germ mealwas placed in a suitable mixer and while mixing, the Drew Oil 1400 wasslowly added and thoroughly mixed.

(2) While mixing continuously the N-acetyl-4(l,2,3, 4,5,6,7,8 octahydro3,3,6,6 tetramethyl-1,8-dioxo-9- xanthenyDbenzenesufonamide was slowlyadded and mixed until the mixture was homogeneous.

(3) This premix was then added to a commercial poultry feed at the ratioof 2 lbs/ton to yield a ratio of 0.0125 percent drug, and thoroughlymixed.

(4) This medicated feed was used in the mash form, and it was alsopelleted on a Sprout-Waldron Pellet Mill.

Amounts of the above premix may be added to the commercial feed to yieldmedicated levels ranging from 0.0025 percent to 0.05 percent. Thecommercial feeds to which the premix is added may be free of othermedicaments or may contain other medicaments if the final mixture iscompatible.

What is claimed is:

1. A compound of the formula SIOzNHz O I ll CH o 0- R2 R2 ReferencesCited UNITED STATES PATENTS 3,454,577 7/1969 Lehr et a1. 260-2793,414,587 12/1968 Lehr et al. 260-335 HENRY R. IILES, Primary ExaminerC. M. SHURKO, Assistant Examiner Tgigg" UNITED STATES PATENT ()FFICECERTIFICATE OF CORRECTION Patent No. 3, 53 1757 Dated October 27, 1970Inventor) Hanna Hanina Lehr and Milan Mitrovic It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

I e I Column 7 claim 1 the formula SO NH a Ra Should be Signed andsealed this 6th day of April 1 971 (SEAL) Attest:

EDWARD M.FLETCIER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

